Characterization of protective immune responses induced by pneumococcal surface protein A in fusion with Pneumolysin derivatives

Pneumococcal surface protein A (PspA) and Pneumolysin derivatives (Pds) are important vaccine candidates, which can confer protection in different models of pneumococcal infection. Furthermore, the combination of these two proteins was able to increase protection against pneumococcal sepsis in mice. The present study investigated the potential of hybrid proteins generated by genetic fusion of PspA fragments to Pds to increase cross-protection against fatal pneumococcal infection. Pneumolisoids were fused to the N-terminus of clade 1 or clade 2 pspA gene fragments. Mouse immunization with the fusion proteins induced high levels of antibodies against PspA and Pds, able to bind to intact pneumococci expressing a homologous PspA with the same intensity as antibodies to rPspA alone or the co-administered proteins. However, when antibody binding to pneumococci with heterologous PspAs was examined, antisera to the PspA-Pds fusion molecules showed stronger antibody binding and C3 deposition than antisera to co-administered proteins. In agreement with these results, antisera against the hybrid proteins were more effective in promoting the phagocytosis of bacteria bearing heterologous PspAs in vitro, leading to a significant reduction in the number of bacteria when compared to co-administered proteins. The respective antisera were also capable of neutralizing the lytic activity of Pneumolysin on sheep red blood cells. Finally, mice immunized with fusion proteins were protected against fatal challenge with pneumococcal strains expressing heterologous PspAs. Taken together, the results suggest that PspA-Pd fusion proteins comprise a promising vaccine strategy, able to increase the immune response mediated by cross-reactive antibodies and complement deposition to heterologous strains, and to confer protection against fatal challenge

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Binary systems and their nuclear explosions

Peer ReviewedPreprin

Avaliação por fotointerpretação das áreas de abrangência dos diferentes estados da erosão acelerada do solo em canaviais e pomares de citros Evaluation of areas of different states of accelerated erosion of soil in sugar cane plantations and citrus orchards utilizing photointerpretation techniques

Este estudo foi realizado com o objetivo de avaliar os estados de erosão acelerada do solo presente em áreas com canaviais e pomares de citros localizados na região administrativa de Ribeirão Preto - SP. Foram empregadas fotografias aéreas verticais, na escala aproximada de 1:40.000, do vôo da cobertura aerofotográfica da região citrícola do Estado de 1988. O estudo foi realizado identificando-se e delimitando-se todas as áreas de abrangência de cinco estados da erosão acelerada do solo presentes nos canaviais e pomares de citros. A presença da erosão acelerada severa a extremamente severa foi constatada tanto nos canaviais como nos pomares de citros, nas quatro unidades de solos de ocorrências principais na área de estudo. Os valores da extensão total das áreas de abrangência dos estados da erosão 2 a 5 (processos erosivos intensos a extremamente intensos) revelaram forte impacto sobre o desenvolvimento das culturas, degradando o solo agrícola e afetando a qualidade da água. As principais diferenças, quanto à extensão total das áreas de abrangência dos diferentes estados da erosão presente, foram identificadas principalmente entre os Argissolos e os Latossolos, e entre os dois estágios de desenvolvimento das culturas. As condições de solo exposto foram verificadas nas áreas recentemente plantadas com cana-de-açúcar ou citros, explicitando-se a grande necessidade de empregar, nessas condições, práticas conservacionistas.<br>This study was conducted with the objective of evaluating the states of accelerated erosion of soil in areas with sugar cane and citrus orchards located in Ribeirão Preto - SP, Brazil, using photointerpretation techniques. Vertical aerial photos, scale of 1:40.000 from the aerophotographic covering of the citric area of the State in 1988 have been used. The map of the land used and accelerated erosion was made in all the areas with five states of the soil accelerated erosion present in the sugar cane plantations and citrus orchards. The study showed the presence of a serious problem caused by the accelerated erosion in the sugar cane plantations and citrus orchards. The presence of areas of severe to extremely severe erosion was verified in the sugar cane plantations and in the citrus orchards, in four soil units, in the study area. The values of the total extension of the areas of the states of erosion 2 to 5 (intense to extremely intense erosive processes) revealed a strong impact of the accelerated erosion on the development of the cultures. This can cause a degradation of the agricultural land and can affect the distribution and quality of the water. The conditions of exposed soil were verified in the areas recently planted with sugar cane or citrus, and those conditions need better agricultural management

Therapeutic possibilities in the autosomal recessive limb-girdle muscular dystrophies

Fourteen years ago, the first disease-causing mutation in a form of autosomal recessive limb-girdle muscular dystrophy was reported. Since then the number of genes has been extended to at least 14 and the phenotypic spectrum has been broadened. The generation of mouse models helped to improve our understanding of the pathogenesis of the disease and also served to study therapeutic possibilities. All autosomal recessive limb-girdle muscular dystrophies are rare diseases, which is one reason why there have been so very few controlled clinical trials. Other reasons are insufficient natural history data and the lack of standardized assessment criteria and validated outcome measures. Currently, therapeutic possibilities are mainly restricted to symptomatic treatment and the treatment of disease complications. On the other hand, new efforts in translational research and the development of molecular therapeutic approaches suggest that more promising clinical trials will be carried out in autosomal recessive limb-girdle muscular dystrophy in the next several years

Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study

Background: Dystroglycanopathy (alpha-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated alpha-dystroglycan. To date, mutations in at least 19 genes have been associated with alpha-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes.We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent alpha-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions.Results: We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants.Conclusion: This work adds to the data on genotype-phenotype correlations in alpha-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders

SEGUE : a spectroscopic survey of 240,000 stars with g=14-20

The Sloan Extension for Galactic Understanding and Exploration (SEGUE) Survey obtained approximate to 240,000 moderate-resolution (R similar to 1800) spectra from 3900 angstrom to 9000 angstrom of fainter Milky Way stars (14.0 10 per resolution element, stellar atmospheric parameters are estimated, including metallicity, surface gravity, and effective temperature. SEGUE obtained 3500 deg(2) of additional ugriz imaging (primarily at low Galactic latitudes) providing precise multicolor photometry (sigma(g, r, i) similar to 2%), (sigma(u, z) similar to 3%) and astrometry (approximate to 0 ''.1) for spectroscopic target selection. The stellar spectra, imaging data, and derived parameter catalogs for this survey are publicly available as part of Sloan Digital Sky Survey Data Release 7